Genetic counseling: Osteosarcoma and Li-Fraumeni Syndrome
Osteosarcoma and Li-Fraumeni Syndrome Contracting *What concerns do you have for yourself or for your family? *What questions do you have? *Overview of agenda **Elicit medical history **Review family history **Discuss genetics, testing, treatment and management Osteosarcoma Background *Most common type of bone cancer **Arises in osteoid tissue in bones **Most common in knees, upper legs, and upper arms **Commonly affects people from ages 10-25 ***Accounts for about 5% of childhood tumors ***50% form in bones around knee ***Only about 30% of patients with localized tumors survive free of relapse *Symptoms of bone cancer **Pain is most common symptom **Other symptoms depend on location and size of tumor ***Tumors in or near joints may cause swelling or tenderness ***Can interfere with normal ability to move **May weaken bones and make fractures more likely **General symptoms include fatigue, fever, weight loss, and anemia *Diagnosis **Alkaline phosphatase assay ***Blood test to determine enzyme levels ***Large amounts of alkaline phosphatase found in blood when cells of bone tissue are active ****During childhood growth ****During mending of broken bone ****When tumor causes production of abnormal bone tissue **X-rays show location, size, and shape of tumor **Bone scan, CT, MRI, or angiogram may be recommended if X-ray suggests that a tumor is cancerous **Biopsy needed to determine for sure if tumor is cancer ***Needle biopsy - make small hole in bone and remove tissue sample from tumor with needle-like instrument ***Incisional biopsy - cut into tumor and remove sample of tissue **No staging system for osteosarcoma so use general terms ***Localized ***Metastatic - most often to lungs or other bones (20% of patients) ***Recurrence - most often in the lungs (5 year survival is 20-40% following surgery) *Treatment **Depends on type, size, location, and stage of cancer **Surgery ***Amputation of limb necessary in some cases ***Pre or post-operative chemotherapy has improved success of limb-sparing surgery ***May remove only cancerous section of bone and replace it with prosthesis **Chemotherapy and radiation may be used alone or together ***Tumors are generally resistant to radiation ***Degree of necrosis following chemotherapy predicts prognosis **Various clinical trials for surgeries, radiation therapies, and chemotherapies *Risk factors for bone cancers **Radiation or chemotherapy treatment in children or young adults for other conditions **Adults with Paget's disease are at increased risk for osteosarcoma **Hereditary factors Li Fraumeni Syndrome Overview *Cancer predisposition syndrome **Associated with soft-tissue sarcomas, breast cancer, leukemia, osteosarcoma, melanoma, and cancer of the colon, pancreas, adrenal cortex, and brain **Increases risk for development of cancers *Diagnosis is made clinically and genetic testing is available Genetic Etiology *Due to mutation in TP53 gene on 17p13 that codes for TP53 protein in more than 50% of cases **Tumor suppressor gene nicknamed "guardian of the genome" **Acts as checkpoint control following DNA damage by delaying cell cycle progression until damaged DNA is repaired or cell commits to apoptosis ***Activates downstream genes to repair DNA ***Signals molecule to confirm damage and proceed with apoptosis **Arrests cell cycle by mediating RB pathway *CHEK2 gene at 22q12.1 also associated with Li-Fraumeni syndrome **Reported in only a few families thus far **Putative tumor suppressor gene ***Lies in TP53 pathway ***One of checkpoint genes activated in response to DNA damage by phorsphorylating p53 **Not known if cancer risks are different than those due to TP53 mutations **Mutations in this gene appear to be most common in osteosarcomas *Autosomal dominant inheritance **Offspring of affected individuals have 50% chance of inheriting mutation **Most individuals diagnosed have an affected parent **De novo mutation rate unknown *Fewer than 400 families reported worldwide *Association of malignancies with TP53 mutations **Less than 1% of all breast cancers **2-10% of childhood brain tumors **50-100% of childhood adrenocortical carcinomas **2-3% of osteosarcomas **9% of rhabdomyosarcomas **7-20% of multiple primaries occurring at young ages *Penetrance **May be as high as 90% **About 25% of cancers occur before age 18 **About 50% of individuals have malignancy by age 40 **About 90% of individuals have malignancy by age 70 **Different studies give different numbers - may be genetic heterogeneity Clinical Features *Predisposes to a number of different types of tumors **Osteosarcomas (23/151) **Soft-tissue sarcomas (32/151) **Pre-menopausal breast cancers (36/151) **Brain tumors - neuroblastoma commonly (14/151) **Adrenal cortical tumors (4/151) **Leukemia - particularly acute leukemia (9/151) *Also associated with excess rates of other cancers **Melanoma **Stomach cancer **Colon cancer **Pancreatic cancer **Esophageal cancer **Gonadal germ cell tumors diagnosed at young ages **Wilm's tumor *Adult women have higher cancer risk than men because of high frequency of breast cancer *Also increases risk to develop multiple primary cancers **Up to 50% may develop second cancer **4% develop third cancer **2% develop four cancers **Survivors of childhood cancer have greatest risk to develop another primary **Radiation exposure appears to increase risk of second cancer *Genotype-phenotype correlation **R337H mutations associate with development of childhood adrenocortical carcinoma as low penetrance allele **13964gc mutation in intron 6 in series of patients with breast cancer as low penetrance allele Diagnosis *Clinical diagnostic criteria (LFS) **Proband with sarcoma diagnosed under 45 years of age **First-degree relative with any cancer under 45 years of age **Third family member who is first- or second-degree relative with cancer under 45 or sarcoma at any age *Li-Fraumeni-like syndrome (LFL) **Share some, but not all features of LFS **Birch's definition ***Proband with any childhood cancer or sarcoma, brain tumor, or adrenal cortical tumor diagnosed under 45 years of age ***First- or second-degree relative with a typical LFS cancer at any age ***Additional first- or second-degree relative with any cancer under the age of 60 **Eele's definition ***Two first- or second-degree relatives with LFS-related malignancies ***Can occur at any age *Molecular genetic testing **Identifies mutations in TP53 gene in about 70% of patients with LFS and 8-22% of families with LFL **DNA sequencing ***Available clinically ***Identifies mutations in about 75% of families ***About 80% of identifiable mutations are in exons 5-8 so testing is often limited to only these exons ***Full gene sequencing and protein function for novel missense mutations generally only offered on research basis **Chip-based DNA sequencing ***Available on research basis only ***Detects most of common single base pair mutations that have been identified ***Sensitivity of 90-98% depending on how much of coding region is sequenced **Can test asymptomatic individuals once mutation is identified in the family ***Cannot predict age of onset, severity, type of cancer, or rate of preogression ***Lack of proven surveillance or prevention so not justified for management but may be useful for reproductive, financial, and career planning or peace of mind ***Testing has been confined to individuals 18 and older since no proven management options **Prenatal testing is possible if mutation identified in family but requires careful genetic counseling **Potential risks of testing ***May not be covered by insurance ***Possible problems with health, life, and disability insurance coverage ***Possible employment and educational discrimination ***Changes in social and family interaction ***Implications for other at-risk family members ***Limitations in management options **Potential benefits of testing ***Explanation for frequent/rare occurrence of cancer in family ***Clarification of risk/relief if individual tests negative for known mutation ***Help make decisions regarding medical management or life decisions **Clinical molecular testing ***City of Hope ****Sequencing of coding exons 2-11 and intron junctions ****Sensitivity estimated to be greater than 95% for point mutations ****Requires 6 cc of whole blood in yellow or lavender topped tube ****Full mutation analysis - $450, known mutation analysis $250 ****Turn-around time is 4 weeks ***University of Pennsylvania ****Conformation sensitive gel electrophoresis (CSGE) ****Shows differences in 2 alleles as small as single base substitution, insertion, deletion ****Sensitivity estimated to be greater than 95% in coding sequence ****Turn-around time is 4 weeks ***Fairview Molecular Diagnostic Laboratory ****Sequencing analysis ****Requires 15 ml blood in yellow topped tube ****Turn-around time is 4-8 weeks Management *No surveillance except breast cancer screening has been show to reduce morbidity and mortality *At-risk individuals should pay attention to signs and symptoms **Lingering aches and illnesses **Headaches, bone pain, abdominal discomfort *Surveillance for at-risk children **Complete physical exam **Urinalysis **Complete blood count **Abdominal ultrasound examination **Additional organ-targeted surveillance based on family history *Surveillance for at-risk adults **Annual complete physical exam including skin, nervous system, rectum, and Pap smear for women **Consider scans of head and abdomen annually **Semi-annual clinical breast exam for women **Annual mammograms, breast ultrasonography, or MRI ***Mammograms controversial because of increased sensitivity to radiation ***Should begin screening by age 25-30 **Additional organ-targeted surveillance based on family history Differential Diagnosis *Hereditary breast/ovarian cancer syndrome *Retinoblastoma - Autosomal dominant **Due to mutations in RB1 gene at 13q14 **RB1 protein is negative regulator of cell growth **Approximately 90% of retinoblastomas occur before age 3 **Increases risk to develop osteosarcoma 500-fold *Rothmund-Thomson syndrome - Autosomal recessive **Due to mutations in RECQL4 gene at 8q24.3 in some families **Cancer risks increased but not quantified **Clinical features include: ***Skin atrophy marbleized pigmentation ***Telangiectasia ***Cataracts ***Osteosarcoma is most commonly reported malignancy *Werner syndrome - Autosomal recessive **Due to mutations in WRN (RECQL2) gene at 8p12 **Cancer risk is 10% lifetime **Clinical features include: ***Multiple complaints of problems associated with aging beginning in 20's and 30's ****Cataracts, graying hair or balding, decreased muscle mass, arteriosclerosis, scleroderma, endocrine failure, and NIDDM ****Also may have lack of growth spurt in puberty or dysmorphic features ***Increased risk for osteosarcoma, soft-tissue sarcoma, melanoma, thyroid cancer, and hematological malignancies References *Hillmann A, et al. "Familial Occurrence of Osteosarcoma: A Case Report and Review of the Literature." J Cancer *Res Clin Oncol (2000) 126: 497-502. *"Li-Fraumeni Syndrome." GeneReviews. http://www.genereviews.org *Lindor NM, et al. "The Concise Handbook of Family Cancer Syndromes." Journal of the National Cancer Institute (1998) 90(14): 1039-1071. *"Osteosarcoma/Malignant Fibrous Histiocytoma of Bone." National Cancer Institute. http://www.cancer.gov *Schneider, Katherine. Counseling about Cancer: Strategies for Genetic Counseling (2002). Notes The information in this outline was last updated in Nov 2002. This material has been imported fom the wikibook "Genetic counseling"[ http://en.wikibooks.org/wiki/Genetic_counseling] under the GNU Free Documentation License.